Current drug discovery programs are increasingly incorporating solution and solid-phase combinatorial chemistry processes to provide large libraries of potentially active compounds. See, for example, Choong, et al., "Solid-Phase Synthesis: Applications to Combinatorial Libraries" in ANNUAL REPORTS IN MEDICINAL CHEMISTRY, Bristol, ed., Academic Press, San Diego, Calif., Volume 31, pp. 309-318 (1996).
A prerequisite for any solid-phase organic synthesis is a method for immobilizing a first building block to a polymeric support. The most commonly used approaches tether a bifunctional building block (e.g., an amino acid) via acylation to an amino- or hydroxy- moiety at the terminus of a cleavable linker. Upon completion of the compound synthesis, the product is cleaved from the support. The product typically carries with it some polar functional group residue (e.g., a carboxamide or carboxylic acid) as a vestige of its site of attachment to the resin. The application of this strategy to the preparation of a combinatorial library of compounds results in each of the compounds having a common functional group (or linker residue). This common functional group in each of the library members can represent a liability as it can potentially impart an undesired common physico-chemical characteristic on an otherwise diverse set of structures.
One approach to the problem of linker residues present in combinatorial libraries is the development of aryl-silane linker groups. These groups can be cleaved from a solid support by strong acid or fluoride ion via ipso hydro-desilation. See, for example, Plunkett, et al., J. Org. Chem. 60:6006 (1995); Chenera, et al., J. Am. Chem. Soc. 117:11999 (1995); Han, et al., Tetrahedron Lett. 37:2703 (1996); and Boehm, et al., J. Org. Chem. 61:6490 (1996). These aryl-silane linker groups have been termed "traceless" linkers since the liberated products contain no obvious signature of the site of their attachment to the solid support. One limitation to existing methods for employing such linkers in construction combinatorial libraries is that a specialized, multi-step synthesis is required for each aromatic building block that is to be tethered to a solid support. Additionally, the use of strong acid or fluoride ion to cleave such linkers is not compatible with a large number of pharmacophore functional groups typically found in combinatorial libraries.
What is needed in the art are new traceless linkers which allow the tethered products to be released using mild procedures such as photolysis. The present invention provides such linkers, methods for their preparation and methods for their use.